Method for the production of beta-ketonitriles

ABSTRACT

The present invention relates to a process for preparing β-ketonitriles of the general formula I 
     
       
         
         
             
             
         
       
     
     in which
         R 1  is, inter alia, C 1 -C 12 -alkyl, C 2 -C 12 -alkenyl, C 2 -C 12 -alkinyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkyl-C 1 -C 4 -alkyl, phenyl-C 1 -C 4 -alkyl, phenoxy-C 1 -C 4 -alkyl or benzyloxy-C 1 -C 4 -alkyl;   R 2  is, inter alia, hydrogen, C 1 -C 12 -alkyl, C 2 -C 12 -alkenyl, C 2 -C 12 -alkinyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkyl-C 1 -C 4 -alkyl, phenyl, phenyl-C 1 -C 4 -alkyl, phenoxy-C 1 -C 4 -alkyl or benzyloxy-C 1 -C 4 -alkyl,
 
which comprises reacting a nitrile of the formula II
       

     
       
         
         
             
             
         
       
     
     in which R 1  has one of the meanings given above with a carboxylic ester of the formula III 
     
       
         
         
             
             
         
       
     
     in which R 2  has one of the meanings given above and R 3  is C 1 -C 12 -alkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkyl-C 1 -C 4 -alkyl, phenyl-C 1 -C 4 -alkyl, phenoxy-C 1 -C 4 -alkyl or benzyloxy-C 1 -C 4 -alkyl,
 
where the reaction is carried out in the presence of a potassium alkoxide and at least  80 % of the nitrile of the formula II are added to the reaction under reaction conditions.

This application is a divisional of U.S. application Ser. No.12/528,700, filed Aug. 26, 2009, which application is a National Stageapplication of International Application No. PCT/EP2008/052514 filedFeb. 29, 2008, the entire contents of which are hereby incorporatedherein by reference. This application also claims the benefit under 35U.S.C. §119 of European Patent Application No. 07103412.8, filed Mar. 2,2007, the entire contents of which is hereby incorporated herein byreference.

The present invention relates to a process for preparing β-ketonitrilesof the general formula I

in which

-   R¹ is C₁-C₁₂-alkyl, C₂-C₁₂-alkenyl, C₂-C₁₂-alkinyl,    C₃-C₈-cycloalkyl, C₃-C₈-cycloalkyl-C₁-C₄-alkyl, phenyl-C₁-C₄-alkyl,    phenoxy-C₁-C₄-alkyl or benzyloxy-C₁-C₄-alkyl, where C₁-C₁₂-alkyl may    be substituted by one of the radicals R^(A), the C₃-C₈-cycloalkyl    groups in the radicals mentioned above may be substituted by 1, 2,    3, 4 or 5 radicals R^(B) and the phenyl groups in the radicals    mentioned above may be substituted by 1, 2, 3, 4 or 5 radicals    R^(C);    -   R^(A) is selected from the group consisting of C₁-C₁₀-alkoxy,        C₁-C₆-alkoxy-C₁-C₄-alkoxy, C₁-C₁₀-alkylthio, NH₂,        C₁-C₁₀-alkylamino and di-C₁-C₁₀-alkylamino;    -   R^(B) is selected from the group consisting of fluorine,        C₁-C₄-alkyl, C₁-C₄-perfluoroalkyl and the meanings given for        R^(A);    -   R^(C) is selected from the group consisting of fluorine, nitro,        C₁-C₄-alkyl, C₁-C₄-perfluoralkyl and the meanings given for        R^(A);-   R² is hydrogen, C₁-C₁₂-alkyl, C₂-C₁₂-alkenyl, C₂-C₁₂-alkinyl,    C₃-C₈-cycloalkyl, C₃-C₈-cycloalkyl-C₁-C₄-alkyl, phenyl,    phenyl-C₁-C₄-alkyl, phenoxy-C₁-C₄-alkyl or benzyloxy-C₁-C₄-alkyl,    where C₁-C₁₂-alkyl may be substituted by one of the radicals R^(A),    the C₃-C₈-cycloalkyl groups in the radicals mentioned above may be    substituted by 1, 2, 3, 4 or 5 radicals R^(B) and the phenyl groups    in the radicals mentioned above may be substituted by 1, 2, 3, 4 or    5 radicals R^(C).    β-Ketonitriles, in particular those of the general formula I, are    interesting starting materials for the preparation of heterocyclic    active compounds, in particular for the preparation of fungicidally    active 7-aminoazolopyrimidines (see, for example, EP-A-141317,    WO2006/087325).    β-Ketonitriles are usually prepared by condensation of nitriles    having hydrogen atoms in the α-position to the nitrile group with    carboxylic esters in the presence of a base. In scheme 1 below, this    reaction is shown for the preparation of the β-ketonitriles of the    formula I. In scheme 1, the variables R¹ and R² have the meanings    mentioned above. R is an inert radical which is attached via a    carbon atom and generally has 1 to 12 carbon atoms.

Thus, for example, EP 141317 describes the preparation of β-acylatedalkyl cyanides by reacting alkyl cyanides with carboxylic esters andstrong bases, for example alkali metal hydrides, alkali metal amides andmetal alkyls. However, such bases are relatively expensive and difficultto handle, making it difficult to transfer this reaction to anindustrial scale.

US2004/0171863, for its part, describes the preparation ofβ-ketonitriles by reacting a carboxylic ester with an alkylnitrile whichcarries two hydrogen atoms in the α-position and a base at temperaturesof from 145 to 300° C. in a closed vessel, which gives the alkali metalsalt of the β-ketonitrile which is then utilized using an acid. However,the reaction conditions stated in this reference give only moderateyields, in particular for nitriles having four or more carbon atoms.

WO2006/087325, for its part, describes the reaction of decanenitrilewith methyl methoxyacetate and potassium tert-butoxide in anhydrousdimethylformamide. The yields found are unsatisfactory. Moreover,applicants' investigations have shown that, when relatively hightemperatures are used, there is an increased formation of byproductswhich are difficult to remove.

Accordingly, it is an object of the present invention to provide aprocess for preparing β-ketonitriles of the general formula I whichsolves the problems of the prior art. In particular, the process is topermit the use of inexpensive alkoxides and to afford the desiredproducts of the formula I in high yield and with good purities.

This object is achieved by a process which comprises reacting a nitrileof the formula II

in which R¹ has one of the meanings mentioned above with a carboxylicester of the formula III

in which R² has one of the meanings mentioned above and R³ isC₁-C₁₂-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, C₃-C₈-cycloalkyl,C₃-C₈-cycloalkyl-C₁-C₄-alkyl, phenyl-C₁-C₄-alkyl, phenoxy-C₁-C₄-alkyl orbenzyloxy-C₁-C₄-alkyl,where the reaction is carried out in the presence of a potassiumalkoxide and at least 80% of the nitrile of the formula II are added tothe reaction under reaction conditions.

The invention therefore provides a process for preparing β-ketonitrilesof the general formula I, as defined at the outset, which comprisesreacting a nitrile of the general formula II with a carboxylic ester ofthe general formula III and which is characterized in that the reactionis carried out in the presence of a potassium alkoxide and at least 80%of the nitrile of the formula II are added to the reaction underreaction conditions.

Even when using potassium alkoxide, which is easy to handle, the processaccording to the invention affords β-ketonitriles in high yields andwith good selectivity. The process according to the invention is inparticular also suitable for preparing β-ketonitriles of the formula Iin which R¹ has three or more carbon atoms, in particular five or morecarbon atoms. Using the reaction sequence shown in Scheme 1, suchβ-ketonitriles can, owing to the reactive inertia of the nitrile parentcompounds of the formula II, only be obtained in poor yields by theroute shown in Scheme 1 and using methods of the prior art, inparticular when the bases used are alkoxides.

In the definitions of the substituents R¹, R², R³, R⁴ and R⁵ and R^(A),R^(B) and R^(C) given in the formulae above and below, collective termswere used which are generally representative for specific organicradicals. Here, in the term C_(n)—C_(m), the variables n and m eachstate the possible number of carbon atoms in the respective radical.Particular meanings are:

Alkyl, and also the alkyl moieties in alkylthio, alkylamino anddialkylamino: a straight-chain or branched hydrocarbon radical havinggenerally one to twelve carbon atoms, or 1 to 4 carbon atoms, 1 to 6carbon atoms or 5 to 12 carbon atoms, such as methyl, ethyl, propyl,1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl,pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl,1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl,1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl,2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl and their isomers,2-ethylhexyl, 3,5,5-trimethylhexyl, 3,5-dimethylhexyl, n-heptyl,1-methylheptyl, 2-methylheptyl, 2-ethylheptyl, 2-propylheptyl, n-octyl,1-methyloctyl, 2-methyloctyl, n-nonyl, 1-methylnonyl, 2-methylnonyl,n-decyl, 1-methyldecyl, n-undecyl, 1-methylundecyl and n-dodecyl.

Correspondingly, alkenyl denotes a straight-chain or branchedethylenically monounsaturated hydrocarbon radical having generally twoto twelve carbon atoms, such as ethenyl, 1-propenyl, 2-propenyl,1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl,2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl,1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl,2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl,2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl,2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl,1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl,1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl,3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl,2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl,1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl,4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl,3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl,1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl,1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl,1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl,2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl,3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl,1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl,2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl,1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl,1-ethyl-2-methyl-2-propenyl, 1-, 2-, 3-, 4-, 5- or 6-heptenyl, 1-, 2-,3-, 4-, 5-, 6- or 7-octenyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-nonenyl,1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-decenyl.

Alkynyl is a straight-chain or branched acetylenically unsaturatedhydrocarbon radical having generally two to twelve carbon atoms, such asethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl,3-methyl-1-butynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl,2-methyl-3-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl,1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl,3-methyl-1-pentynyl, 4-methyl-1-pentynyl, 1-methyl-2-pentynyl,4-methyl-2-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl,1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl,1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl,2,2-dimethyl-3-butynyl, 3,3-dimethyl-1-butynyl, 1-ethyl-2-butynyl,1-ethyl-3-butynyl, 1-ethyl-1-methyl-2-propynyl, 1-, 2-, 3-, 4-, 5- or6-heptynyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-octynyl, 1-, 2-, 3-, 4-, 5-, 6-,7- or 8-nonynyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-decynyl.

Cycloalkyl is a mono- or bicyclic hydrocarbon radical having generallythree to eight carbon atoms, such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[3.3.0]octyl,bicyclo[2.2.1]heptyl and bicyclo[3.2.1]octyl.

Cycloalkyl-C₁-C₄-alkyl is an alkyl radical having one to four carbonatoms which carries a cycloalkyl radical as defined above havingpreferably three to eight carbon atoms.

Phenyl-C₁-C₄-alkyl is an alkyl radical having one to four carbon atomswhich carries a phenyl radical, and is, for example, benzyl,1-phenylethyl or 2-phenylethyl.

Phenoxy-C₁-C₄-alkyl is an alkyl radical having one to four carbon atomswhich carries a phenoxy radical as substituent. Correspondingly,benzyloxy-C₁-C₄-alkyl denotes an alkyl radical having one to four carbonatoms which carries a benzyloxy radical.

Alkoxy is an alkyl radical having one to ten and in particular one toeight carbon atoms which is attached via oxygen, such as methoxy,ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy,2-methylpropoxy, 1,1-dimethylethoxy, pentoxy, 1-methylbutoxy,2-methylbutoxy, 3-methylbutoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy,hexyloxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 1-methylpentyloxy,2-methylpentyloxy, 3-methylpentyloxy, 4-methylpentyloxy,1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy,2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy,1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy,1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy, 1-ethyl-2-methylpropoxyand their isomers, 2-ethylhexyloxy, 3,5,5-trimethylhexyloxy,3,5-dimethylhexyloxy, n-heptyloxy, 1-methylheptyloxy, 2-methylheptyloxy,2-ethylheptyloxy, 2-propylheptyloxy, n-octyloxy, 1-methyloctyloxy,2-methyloctyloxy, n-nonyloxy, 1-methylnonyloxy, 2-methylnonyloxy andn-decyloxy.

Correspondingly, alkylthio is a straight-chain or branched alkyl radicalhaving generally one to ten carbon atoms which is attached via sulfuratom.

Alkylamino is a straight-chain or branched alkyl radical having one toeight carbon atoms which is attached via an NH group. Correspondingly,dialkylamino is a group NR₂ in which R may be identical or different andis straight-chain or branched alkyl having generally one to ten carbonatoms.

Alkoxyalkyl is an alkyl radical having generally one to four carbonatoms which carries an alkoxy radical as defined above, for examplemethoxymethyl, ethoxymethyl, —CH₂OCH₂—C₂H₅, —CH₂—OCH(CH₃)₂,n-butoxymethyl, —CH₂—OCH(CH₃)—C₂H₅, —CH₂—OCH₂—CH(CH₃)₂, —CH₂—OC(CH₃),methoxyethyl, ethoxyethyl, —(CH₂)₂OCH₂—C₂H₅, —(CH₂)₂OCH(CH₃)₂,n-butoxyethyl, —(CH₂)₂OCH(CH₃)—C₂H₅, —(CH₂)₂OCH₂—CH(CH₃)₂ or—(CH₂)₂—OC(CH₃), 1-methylbutoxymethyl, 2-methylbutoxymethyl,3-methylbutoxymethyl, 2,2-dimethylpropoxymethyl, 1-ethylpropoxymethyl,hexyloxymethyl, 1,1-dimethylpropoxymethyl, 1,2-dimethylpropoxymethyl,1-methylpentyloxymethyl, 2-methylpentyloxymethyl,3-methylpentyloxymethyl, 4-methylpentyloxymethyl,1,1-dimethylbutoxymethyl, 1,2-dimethylbutoxymethyl,1,3-dimethylbutoxymethyl, 2,2-dimethylbutoxymethyl,2,3-dimethylbutoxymethyl, 3,3-dimethylbutoxymethyl, 1-ethylbutoxymethyl,2-ethylbutoxymethyl, 1,1,2-trimethylpropoxymethyl,1,2,2-trimethylpropoxymethyl, 1-ethyl-1-methylpropoxymethyl,1-ethyl-2-methylpropoxymethyl and their isomers, 2-ethylhexyloxymethyl,3,5,5-trimethylhexyloxymethyl, 3,5-dimethylhexyloxymethyl,n-heptyloxymethyl, 1-methylheptyloxymethyl, 2-methylheptyloxymethyl,2-ethylheptyloxymethyl, 2-propylheptyloxymethyl, n-octyloxymethyl,1-methyloctyloxymethyl, 2-methyloctyloxymethyl, n-nonyloxymethyl,1-methylnonyloxymethyl, 2-methylnonyloxymethyl, n-decyloxymethyl,1-(1-methylbutoxy)ethyl, 1-(2-methylbutoxy)ethyl,1-(3-methylbutoxy)ethyl, 1-(2,2-dimethylpropoxy)ethyl,1-(1-ethylpropoxy)ethyl, 1-(hexyloxy)ethyl,1-(1,1-dimethylpropoxy)ethyl, 1-(1,2-dimethylpropoxy)ethyl,1-(1-methylpentyloxy)ethyl, 1-(2-methylpentyloxy)ethyl,1-(3-methylpentyloxy)ethyl, 1-(4-methylpentyloxy)ethyl,1-(1,1-dimethylbutoxy)ethyl, 1-(1,2-dimethylbutoxy)ethyl,1-(,3-dimethylbutoxy)ethyl, 1-(2,2-dimethylbutoxy)ethyl,1-(2,3-dimethylbutoxy)ethyl, 1-(3,3-dimethylbutoxy)ethyl,1-(1-ethylbutoxy)ethyl, 1-(2-ethylbutoxy)ethyl,1-(2-ethylhexyloxy)ethyl, 1-(3,5,5-trimethylhexyloxy)ethyl,1-(3,5-dimethylhexyloxy)ethyl, 1-(n-heptyloxy)ethyl,1-(1-methylheptyloxy)ethyl, 1-(2-propylheptyloxy)ethyl,1-(n-octyloxy)ethyl, 1-(1-methyloctyloxy)ethyl,1-(2-methyloctyloxy)ethyl, 1-(n-nonyloxy)ethyl,1-(1-methylnonyloxy)ethyl, 1-(2-methylnonyloxy)ethyl,1-(n-decyloxy)ethyl, 2-(1-methylbutoxy)ethyl, 2-(2-methylbutoxy)ethyl,2-(3-methylbutoxy)ethyl, 2-(2,2-dimethylpropoxy)ethyl,2-(1-ethylpropoxy)ethyl, 2-(hexyloxy)ethyl,2-(1,1-dimethylpropoxy)ethyl, 2-(1,2-dimethylpropoxy)ethyl,2-(1-methylpentyloxy)ethyl, 2-(2-methylpentyloxy)ethyl,2-(3-methylpentyloxy)ethyl, 2-(4-methylpentyloxy)ethyl,2-(1,1-dimethylbutoxy)ethyl, 2-1,2-dimethylbutoxy)ethyl,2-(,3-dimethylbutoxy)ethyl, 2-(2,2-dimethylbutoxy)ethyl,2-(2,3-dimethylbutoxy)ethyl, 2-(3,3-dimethylbutoxy)ethyl,2-(1-ethylbutoxy)ethyl, 2-(2-ethylbutoxy)ethyl,2-(2-ethylhexyloxy)ethyl, 2-(3,5,5-trimethylhexyloxy)ethyl,2-(3,5-dimethylhexyloxy)ethyl, 2-(n-heptyloxy)ethyl,2-(1-methylheptyloxy)ethyl, 2-(2-propylheptyloxy)ethyl,2-(n-octyloxy)ethyl, 2-(1-methyloctyloxy)ethyl,2-(2-methyloctyloxy)ethyl, 2-(n-nonyloxy)ethyl,2-(1-methylnonyloxy)ethyl, 2-(2-methylnonyloxy)ethyl and2-(n-decyloxy)ethyl.

Alkoxyalkoxy is an alkoxy radical having generally one to four carbonatoms which carries an alkoxy radical as defined above, for examplemethoxymethoxy, ethoxymethoxy, —OCH₂OCH₂—C₂H₅, —OCH₂—OCH(CH₃)₂,n-butoxymethoxy, —OCH₂—OCH(CH₃)—C₂H₅, —OCH₂—OCH₂—CH(CH₃)₂,—OCH₂—OC(CH₃), methoxyethoxy, ethoxyethoxy, —O(CH₂)₂OCH₂—C₂H₅,—O(CH₂)₂OCH(CH₃)₂, n-butoxyethoxy, —O(CH₂)₂OCH(CH₃)—C₂H₅,—O(CH₂)₂OCH₂—CH(CH₃)₂ or —O(CH₂)₂—OC(CH₃), etc.

Perfluoralkyl is an alkyl radical having generally one to four carbonatoms in which the hydrogen atoms are replaced by fluorine atoms.Examples of perfluoroalkyl are in particular trifluoromethyl,pentafluoroethyl, heptafluoropropyl, etc.

According to the invention, when reacting the nitrile of the formula IIwith the carboxylic ester of the formula III, at least 80%, inparticular at least 90%, particularly preferably at least 95% andespecially the total amount of at least 99% of the nitrile of theformula II are added to the reaction under reaction conditions.

The term “under reaction conditions” is familiar to the person skilledin the art and means that in the reaction vessel or in the reaction zonein which the desired reaction is carried out, the conditions present aresuch that the desired reaction proceeds at a satisfactory reaction rate.In the process according to the invention, this means that in thereaction vessel or in the reaction zone in which the reaction of thenitrile II with the ester III is carried out are temperatures at which,in the presence of the potassium alkoxide, a reaction of the nitrile IIwith the carboxylic ester III with formation of the potassium salt ofthe compound I can proceed at a rate which is sufficient for thereaction.

The temperatures required for the reaction can be determined by theperson skilled in the art by routine experiments and are usually atleast 50° C., in particular at least 80° C. and particularly preferablyat least 100° C. The reaction temperatures will generally not exceed200° C. and are preferably in the range of from 80 to 180° C. andespecially in the range of from 110 to 150° C.

The reaction pressure is of minor importance for the reaction. Ingeneral, the reaction is carried out in reactors where the pressure isequalized with the atmospheric pressure, so that the reaction is carriedout at atmospheric pressure. For technical reasons, it may also beadvantageous to carry out the reaction at slightly reduced pressure, forexample in the range of from 0.9 bar (absolute) to atmospheric pressure,or at slightly elevated pressure, for example in the range of fromatmospheric pressure to 3.0 bar (absolute).

The desired amount of nitrile can be added in one or more portions orcontinuously over a relatively long period of time at a constant orchanging rate of addition. Frequently, the amount of nitrile addedduring the course of the reaction will be added over a certain period oftime, generally in the range of from five minutes to one hour and inparticular in the range of from ten minutes to thirty minutes.

For the process according to the invention, it has furthermore beenfound to be advantageous to add the major amount, in particular at least80%, of the carboxylic ester of the formula III to the reaction underreaction conditions. According to a first preferred embodiment of theinvention, at least 90% and in particular at least 95% and particularlypreferably the total amount or at least 99% of the carboxylic ester ofthe formula III are added under reaction conditions. According toanother preferred embodiment, from 1 to 20% by weight and in particularfrom 5 to 15% by weight of the carboxylic ester are initially charged inthe reaction vessel, and the remaining amount of carboxylic ester isadded under reaction conditions.

If the major amount of the carboxylic ester of the formula III is addedduring the course of the reaction, the addition may also be in oneportion, in a plurality of portions or over a relatively long period oftime continuously at a constant or changing rate of addition.Preferably, the desired amount of carboxylic ester III is added over acertain period of time which is generally from five minutes to one hourand in particular from ten minutes to thirty minutes.

The reaction of the nitrile II with the carboxylic ester III ispreferably carried out in an inert solvent. Examples of suitable inertsolvents are aliphatic and cycloaliphatic hydrocarbons, such as hexane,heptane, octane, cyclohexane, cycloheptane and cyclooctane, aromatichydrocarbons, in particular alkylaromatics, such as toluene, xylenes,1,2-, 1,3- and 1,4-dimethylbenzene and mixtures thereof, mesitylene,ethylbenzene, isopropylbenzene (cumene), 1,2-, 1,3- and1,4-methylisopropylbenzene (cymenes) and mixtures thereof, 1,3- and1,4-diisopropylbenzene and mixtures thereof, 1,2-, 1,3- and1,4-diethylbenzene and mixtures thereof, furthermore dialkyl ethers andalicyclic ethers, such as di-n-propyl ether, diisopropyl ether, methyltert-butyl ether, ethyl tert-butyl ether, ethylene glycol dimethylether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether,triethylene glycol dimethyl ether, tetrahydrofuran,2-methyltetrahydrofuran, dioxane and tetrahydropyran. Also suitable aremixtures of the inert solvents mentioned above.

Preferred inert solvents are the alkylaromatics mentioned above andmixtures thereof with inert solvents different therefrom, for examplewith aliphatic and alicyclic hydrocarbons or the ethers mentioned above.Preferably, the inert solvent comprises at least 80% by weight and inparticular at least 90% by weight, based on the total amount of inertsolvent, of one or more alkylaromatics or a mixture of at least onealkylaromatic with one or more aliphatic or cycloaliphatic hydrocarbons.Very particularly preferably, the inert solvent comprises at least 80%by weight and in particular at least 90% by weight of alkylaromatics, inparticular xylene or mesitylene. Preferably, the solvent or solventmixture has a boiling point in the temperature range mentioned above.

The amount of solvent is generally chosen such that the total amount ofmaterials used (i.e. the total concentration of compounds II, III andpotassium alkoxide) is in the range of from 20 to 80% by weight, inparticular in the range of from 30 to 70% by weight, based on the totalamount of materials used and solvents.

According to the invention, the reaction is carried out in the presenceof a potassium alkoxide. Here, the potassium alkoxide serves as base. Ifappropriate, small amounts of other bases may also be present during thereaction. In general, at least 70% by weight, preferably at least 80% byweight and in particular at least 90% by weight of the base employed arepotassium alkoxide. Suitable potassium alkoxides are in particular thepotassium salts of C₁-C₆-alkanols, such as potassium methoxide,potassium ethoxide, potassium propoxide, potassium n-butoxide, potassiumtert-butoxide, potassium 2-butoxide and potassium (2-methyl-2-butoxide).The potassium alkoxides can also be employed in the form of mixtures.Suitable further bases are in particular sodium salts and potassiumsalts of weak acids, such as sodium hydroxide and potassium hydroxide,sodium carbonate and potassium carbonate, sodium alkoxides, inparticular the sodium salts of C₁-C₆-alkanoles and the like, but alsosodium hydride and potassium hydride. Preferably, at least 95%, inparticular at least 98%, based on the total amount of base employed, arepotassium alkoxide. Small amounts of potassium hydroxide resulting fromthe hydrolysis of the potassium alkoxide don't generally interfere.However, preferably their proportion is not more than 3% by weight andin particular not more than 1.5% by weight, based on the total amount ofbase.

The amount an potassium alkoxide employed is preferably at least 0.9mol, in particular at least 1 mol and particularly preferably at least1.1 mol per mole of nitrile of the formula II. The amount of potassiumalkoxide may also be 2.5, 3 or 4 mol or more per mole of the nitrile IIsince larger amounts of base generally don't have any disadvantageouseffect on the reaction. Preferably, the molar ratio of potassiumalkoxide to the total amount of nitrile of the formula II is in therange of from 1.1:1 to 4:1, in particular from 2:1 to 4:1.

It has furthermore been found to be advantageous for the reaction if theorganic solvent employed for the reaction comprises small amounts of aC₁-C₄-alkanol. The amount of C₁-C₄-alkanol is generally not more than 50mol % and in particular not more than mol % and is, for example, in therange of from 1 to 50 mol % or from 1 to 20 mol %, based on the totalamount of the ester of the formula III employed in the reaction. Here,it has been found to be advantageous to initially charge this amount ofalkanol in the reaction vessel.

The molar ratio of nitrile of the formula II to ester of the formula IIIis typically in the range of from 1:3 to 1.5:1, preferably in the rangeof from 1:2 to 1:1 and in particular in the range of from 1:1.1 to1:1.5.

The reaction is carried out in reaction vessels customary for thispurpose which are generally provided with conventional means for mixingthe reactants, for example stirrers, means for adding the reactants ofthe formulae II and III, means for controlling the reaction temperatureand the reaction pressure and the like. The reaction can be carried outcontinuously or discontinuously, i.e. batch-wise, the latter beingpreferred.

In the customary batch-wise reaction, the reaction is usually carriedout in a reaction vessel provided with means for adding the nitrile ofthe formula II and, if appropriate, the ester of the formula III, andwith suitable means for mixing the reactants, for example stirrers. Thereaction can be carried out at atmospheric pressure or at elevatedpressure. In general, in the batch-wise reaction, a partial amount orthe total amount of the potassium alkoxide, preferably at least 80%,based on the total amount of potassium alkoxide, is initially charged inthe reaction vessel, if appropriate with a partial amount or the totalamount of inert solvent and, if appropriate, a partial amount or thetotal amount of the ester of the formula III, if appropriate up to 20%of the nitrile of the formula II and, if appropriate, the C₁-C₄-alkanol.The mixture obtained in this manner is then heated to reactiontemperature, and the addition of the remaining amount of potassiumalkoxide and the remaining amount of inert solvent is then initiated.Preferably, all of the alkoxide and all of the inert solvent, ifdesired, are initially charged in the reactor. If a partial amount or inparticular the major amount of the ester of the formula III is addedunder reaction conditions, the addition of III is preferably carried outin parallel to the addition of the nitrile II, i.e. the start and theend of the addition of the ester III does not differ from, or only by afew minutes, the beginning and the end of the addition of the nitrile ofthe formula II (frequently no more than 5 min., in particular no morethan 2 min.). In particular, the addition of the nitrile II and theaddition of the esters III are initiated simultaneously (<±2 min.), andalso ended simultaneously (<±2 min.). In general, following thetermination of the addition of the nitrile II and, if appropriate, theester III, there is a post-reaction phase during which the reactionmixture is kept at the reaction temperature for a certain period oftime. In general, this period of time is at least thirty minutes andwill generally not exceed 24 hours. In particular, this in the range offrom 1 to 12 hours and especially in the range of from 2 to 8 hours.

After the reaction has ended, the reaction mixture can be worked up in acustomary manner and the β-ketonitrile of the formula I can be isolated,if required.

For work-up of the reaction mixture, the potassium salt initially formedof the β-ketonitrile of the general formula I and any alkoxide presentwill generally be neutralized. To this end, the reaction mixture ismixed with water or an aqueous acid, for example an aqueous hydrochloricacid or an aqueous sulfuric acid. Preferably, during mixing, the pH ismonitored, and the pH should not be lower than a value of preferablypH=2 and in particular a value of pH=3. To this end, a procedure may beadopted, for example, where a dilute aqueous acid is introduced into thereaction mixture in an amount such that the pH of the resulting aqueousphase is in the range of from pH 2 to 9 and in particular in the rangeof pH 3 to 8. Alternatively, the reaction mixture may be introduced intowater or into an aqueous acid, and the pH of the aqueous phase may, ifrequired, be readjusted by addition of acid to a pH in the range of pH 2to 9 and in particular pH 3 to 8. The organic phase now comprises thedesired β-ketonitrile of the formula I, if appropriate dissolved in anorganic solvent.

After drying, if appropriate, the β-ketonitrile of the formula I can beisolated in a customary manner from the organic phase, for example bydistilling off the organic solvent. The β-ketonitrile that remains canthen be subjected to a further purification. However, it has been foundthat, under the reaction conditions according to the invention, theβ-ketonitrile of the formula I is obtained in a purity which isgenerally sufficient for further reactions. Frequently, even a removalof the organic solvent can be dispensed with.

The process according to the invention is suitable in particular forpreparing β-ketonitriles of the general formula I in which R¹ is asubstituent which carries at least four carbon atoms. In the formulae Iand II, R¹ is in particular C₄-C₁₂-alkyl, C₃-C₁₂-alkenyl, benzyl,C₅-C₈-cycloalkyl or C₁-C₁₀-alkoxy-C₁-C₆-alkyl. Particularly preferably,R¹ is C₆-C₁₂-alkyl. R¹ is likewise preferably C₃-C₁₂-alkenyl.

In particular, the process according to the invention is suitable forpreparing β-ketonitriles of the general formula I in which R² isC₁-C₈-alkyl, CF₃, C₃-C₈-cycloalkyl or C₁-C₄-alkoxy-C₁-C₄-alkyl. In theformulae I and III, R² is in particular C₁-C₈-alkyl and especiallyC₁-C₄-alkyl. According to another embodiment which is likewisepreferred, R² in the formulae I and III is C₁-C₆-alkoxy-C₁-C₄-alkyl andin particular C₁-C₄-alkoxymethyl or 2-C₁-C₄-alkoxyethyl.

Examples of suitable β-ketonitriles of the formula I are the compoundsof the general formula I listed in Table 1 in which R¹ and R² each havethe meanings given in one row of the table:

TABLE 1 R¹ R² I-1 CH₂—C₆H₅ CH₃ I-2 CH₂CH₂CH₃ CH₃ I-3 CH₂CH₂CH₂CH₃ CH₃I-4 CH₂CH₂CH₂CH₂CH₃ CH₃ I-5 CH₂CH₂CH₂CH₂CH₂CH₃ CH₃ I-6CH₂CH(CH₃)CH₂CH₂CH₃ CH₃ I-7 CH₂CH(CH₂CH₃)₂ CH₃ I-8 CH₂CH₂CH₂CH₂CH₂CH₂CH₃CH₃ I-9 CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₃ I-10 CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃CH₃ I-11 CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₃ I-12 CH₂CH₂CH(CH₃)CH₂C(CH₃)₃CH₃ I-13 CH₂CH₂C(CH₃)₂CH₂C(CH₃)₃ CH₃ I-14 (CH₂)₃—O—CH₃ CH₃ I-15(CH₂)₃—O—CH₂CH₃ CH₃ I-16 (CH₂)₃—O—CH₂CH₂CH₃ CH₃ I-17(CH₂)₃—O—CH₂CH₂CH₂CH₃ CH₃ I-18 (CH₂)₃—O—CH₂CH₂CH₂CH₂CH₃ CH₃ I-19(CH₂)₃—O—CH₂CH₂CH₂CH₂CH₂CH₃ CH₃ I-20 (CH₂)₃—O—CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₃I-21 (CH₂)₃—O—CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₃ I-22 (CH₂)₃—O—(CH₂)₈CH₃ CH₃I-23 (CH₂)₃—O—CH(CH₃)₂ CH₃ I-24 (CH₂)₃—O—C(CH₃)₃ CH₃ I-25(CH₂)₃—O—CH₂C(CH₃)₃ CH₃ I-26 (CH₂)₃—O—CH(CH₃)CH₂C(CH₃)₃ CH₃ I-27(CH₂)₃—O—CH(CH₂CH₃)CH₂C(CH₃)₃ CH₃ I-28 (CH₂)₃—O—CH₂CH(CH₃)CH₂CH(CH₃)₂CH₃ I-29 (CH₂)₃—O—CH₂CH(CH₂CH₃)CH₂CH₂CH₃ CH₃ I-30(CH₂)₃—O—CH₂CH₂CH(CH₃)CH₂CH(CH₃)₂ CH₃ I-31(CH₂)₃—O—CH₂CH₂CH(CH₃)CH₂C(CH₃)₃ CH₃ I-32(CH₂)₃—O—CH₂CH₂CH(CH₃)CH₂CH₂CH(CH₃)₂ CH₃ I-33(CH₂)₃—O—CH₂CH₂CH(CH₃)(CH₂)₃CH(CH₃)₂ CH₃ I-34 cyclo-C₅H₉ CH₃ I-35cyclo-C₆H₁₁ CH₃ I-36 CH₂—C₆H₅ CF₃ I-37 CH₂CH₂CH₃ CF₃ I-38 CH₂CH₂CH₂CH₃CF₃ I-39 CH₂CH₂CH₂CH₂CH₃ CF₃ I-40 CH₂CH₂CH₂CH₂CH₂CH₃ CF₃ I-41CH₂CH(CH₃)CH₂CH₂CH₃ CF₃ I-42 CH₂CH(CH₂CH₃)₂ CF₃ I-43CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CF₃ I-44 CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CF₃ I-45CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CF₃ I-46 CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CF₃I-47 CH₂CH₂CH(CH₃)CH₂C(CH₃)₃ CF₃ I-48 CH₂CH₂C(CH₃)₂CH₂C(CH₃)₃ CF₃ I-49cyclo-C₅H₉ CF₃ I-50 cyclo-C₆H₁₁ CF₃ I-51 CH₂CH₂CH₂CH₃ CH₂CH₃ I-52CH₂CH₂CH₂CH₂CH₃ CH₂CH₃ I-53 CH₂CH₂CH₂CH₂CH₂CH₃ CH₂CH₃ I-54CH₂CH(CH₃)CH₂CH₂CH₃ CH₂CH₃ I-55 CH₂CH(CH₂CH₃)₂ CH₂CH₃ I-56CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₂CH₃ I-57 CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₂CH₃ I-58CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₂CH₃ I-59 CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃CH₂CH₃ I-60 CH₂CH₂CH(CH₃)CH₂C(CH₃)₃ CH₂CH₃ I-61 CH₂CH₂C(CH₃)₂CH₂C(CH₃)₃CH₂CH₃ I-62 (CH₂)₃—O—CH₃ CH₂CH₃ I-63 (CH₂)₃—O—CH₂CH₃ CH₂CH₃ I-64(CH₂)₃—O—CH₂CH₂CH₃ CH₂CH₃ I-65 (CH₂)₃—O—CH₂CH₂CH₂CH₃ CH₂CH₃ I-66(CH₂)₃—O—CH₂CH₂CH₂CH₂CH₃ CH₂CH₃ I-67 (CH₂)₃—O—CH₂CH₂CH₂CH₂CH₂CH₃ CH₂CH₃I-68 (CH₂)₃—O—CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₂CH₃ I-69(CH₂)₃—O—CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₂CH₃ I-70 (CH₂)₃—O—(CH₂)₈CH₃ CH₂CH₃I-71 (CH₂)₃—O—CH(CH₃)₂ CH₂CH₃ I-72 (CH₂)₃—O—C(CH₃)₃ CH₂CH₃ I-73(CH₂)₃—O—CH₂C(CH₃)₃ CH₂CH₃ I-74 (CH₂)₃—O—CH(CH₃)CH₂C(CH₃)₃ CH₂CH₃ I-75(CH₂)₃—O—CH(CH₂CH₃)CH₂C(CH₃)₃ CH₂CH₃ I-76 (CH₂)₃—O—CH₂CH(CH₃)CH₂CH(CH₃)₂CH₂CH₃ I-77 (CH₂)₃—O—CH₂CH(CH₂CH₃)CH₂CH₂CH₃ CH₂CH₃ I-78(CH₂)₃—O—CH₂CH₂CH(CH₃)CH₂CH(CH₃)₂ CH₂CH₃ I-79(CH₂)₃—O—CH₂CH₂CH(CH₃)CH₂C(CH₃)₃ CH₂CH₃ I-80(CH₂)₃—O—CH₂CH₂CH(CH₃)CH₂CH₂CH(CH₃)₂ CH₂CH₃ I-81(CH₂)₃—O—CH₂CH₂CH(CH₃)(CH₂)₃CH(CH₃)₂ CH₂CH₃ I-82 CH₂CH₂CH₂CH₃ CH₂CH₂CH₃I-83 CH₂CH₂CH₂CH₂CH₃ CH₂CH₂CH₃ I-84 CH₂CH₂CH₂CH₂CH₂CH₃ CH₂CH₂CH₃ I-85CH₂CH(CH₃)CH₂CH₂CH₃ CH₂CH₂CH₃ I-86 CH₂CH(CH₂CH₃)₂ CH₂CH₂CH₃ I-87CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₂CH₂CH₃ I-88 CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₂CH₂CH₃I-89 CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₂CH₂CH₃ I-90CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₂CH₂CH₃ I-91 CH₂CH₂CH(CH₃)CH₂C(CH₃)₃CH₂CH₂CH₃ I-92 CH₂CH₂C(CH₃)₂CH₂C(CH₃)₃ CH₂CH₂CH₃ I-93 CH₂—O—CH₂CH₂CH₂CH₃CH₂CH₂CH₃ I-94 CH₂—O—CH₂CH₂CH₂CH₂CH₃ CH₂CH₂CH₃ I-95CH₂—O—CH₂CH₂CH₂CH₂CH₂CH₃ CH₂CH₂CH₃ I-96 CH₂—O—CH₂CH₂CH₂CH₂CH₂CH₂CH₃CH₂CH₂CH₃ I-97 CH₂—O—CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₂CH₂CH₃ I-98CH₂—O—CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₂CH₂CH₃ I-99 CH₂—O—C(CH₃)₃ CH₂CH₂CH₃I-100 CH₂—O—CH₂C(CH₃)₃ CH₂CH₂CH₃ I-101 CH₂—O—CH(CH₃)CH₂C(CH₃)₃ CH₂CH₂CH₃I-102 CH₂—O—CH(CH₂CH₃)CH₂C(CH₃)₃ CH₂CH₂CH₃ I-103CH₂—O—CH₂CH(CH₃)CH₂CH(CH₃)₂ CH₂CH₂CH₃ I-104 CH₂—O—CH₂CH(CH₂CH₃)CH₂CH₂CH₃CH₂CH₂CH₃ I-105 CH₂—O—CH₂CH₂CH(CH₃)CH₂CH(CH₃)₂ CH₂CH₂CH₃ I-106CH₂—O—CH₂CH₂CH(CH₃)CH₂C(CH₃)₃ CH₂CH₂CH₃ I-107CH₂—O—CH₂CH₂CH(CH₃)CH₂CH₂CH(CH₃)₂ CH₂CH₂CH₃ I-108CH₂—O—CH₂CH₂CH(CH₃)(CH₂)₃CH(CH₃)₂ CH₂CH₂CH₃ I-109 (CH₂)₂—O—CH₂CH₂CH₃CH₂CH₂CH₃ I-110 (CH₂)₂—O—CH₂CH₂CH₂CH₃ CH₂CH₂CH₃ I-111(CH₂)₂—O—CH₂CH₂CH₂CH₂CH₃ CH₂CH₂CH₃ I-112 (CH₂)₂—O—CH₂CH₂CH₂CH₂CH₂CH₃CH₂CH₂CH₃ I-113 (CH₂)₂—O—CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₂CH₂CH₃ I-114(CH₂)₂—O—CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₂CH₂CH₃ I-115 (CH₂)₂—O—(CH₂)₈CH₃CH₂CH₂CH₃ I-116 (CH₂)₂—O—CH(CH₃)₂ CH₂CH₂CH₃ I-117 (CH₂)₂—O—C(CH₃)₃CH₂CH₂CH₃ I-118 (CH₂)₂—O—CH₂C(CH₃)₃ CH₂CH₂CH₃ I-119(CH₂)₂—O—CH(CH₃)CH₂C(CH₃)₃ CH₂CH₂CH₃ I-120 (CH₂)₂—O—CH(CH₂CH₃)CH₂C(CH₃)₃CH₂CH₂CH₃ I-121 (CH₂)₂—O—CH₂CH(CH₃)CH₂CH(CH₃)₂ CH₂CH₂CH₃ I-122(CH₂)₂—O—CH₂CH(CH₂CH₃)CH₂CH₂CH₃ CH₂CH₂CH₃ I-123(CH₂)₂—O—CH₂CH₂CH(CH₃)CH₂CH(CH₃)₂ CH₂CH₂CH₃ I-124(CH₂)₂—O—CH₂CH₂CH(CH₃)CH₂C(CH₃)₃ CH₂CH₂CH₃ I-125(CH₂)₂—O—CH₂CH₂CH(CH₃)CH₂CH₂CH(CH₃)₂ CH₂CH₂CH₃ I-126(CH₂)₃—O—CH₂CH₂CH(CH₃)(CH₂)₃CH(CH₃)₂ CH₂CH₂CH₃ I-127 (CH₂)₃—O—CH₃CH₂CH₂CH₃ I-128 (CH₂)₃—O—CH₂CH₃ CH₂CH₂CH₃ I-129 (CH₂)₃—O—CH₂CH₂CH₃CH₂CH₂CH₃ I-130 (CH₂)₃—O—CH₂CH₂CH₂CH₃ CH₂CH₂CH₃ I-131(CH₂)₃—O—CH₂CH₂CH₂CH₂CH₃ CH₂CH₂CH₃ I-132 (CH₂)₃—O—CH₂CH₂CH₂CH₂CH₂CH₃CH₂CH₂CH₃ I-133 (CH₂)₃—O—CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₂CH₂CH₃ I-134(CH₂)₃—O—CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₂CH₂CH₃ I-135 (CH₂)₃—O—(CH₃)₈CH₃CH₂CH₂CH₃ I-136 (CH₂)₃—O—CH(CH₃)₂ CH₂CH₂CH₃ I-137 (CH₂)₃—O—C(CH₃)₃CH₂CH₂CH₃ I-138 (CH₂)₃—O—CH₂C(CH₃)₃ CH₂CH₂CH₃ I-139(CH₂)₃—O—CH(CH₃)CH₂C(CH₃)₃ CH₂CH₂CH₃ I-140 (CH₂)₃—O—CH(CH₂CH₃)CH₂C(CH₃)₃CH₂CH₂CH₃ I-141 (CH₂)₃—O—CH₂CH(CH₃)CH₂CH(CH₃)₂ CH₂CH₂CH₃ I-142(CH₂)₃—O—CH₂CH(CH₂CH₃)CH₂CH₂CH₃ CH₂CH₂CH₃ I-143(CH₂)₃—O—CH₂CH₂CH(CH₃)CH₂CH(CH₃)₂ CH₂CH₂CH₃ I-144(CH₂)₃—O—CH₂CH₂CH(CH₃)CH₂C(CH₃)₃ CH₂CH₂CH₃ I-145(CH₂)₃—O—CH₂CH₂CH(CH₃)CH₂CH₂CH(CH₃)₂ CH₂CH₂CH₃ I-146(CH₂)₃—O—CH₂CH₂CH(CH₃)(CH₂)₃CH(CH₃)₂ CH₂CH₂CH₃ I-147 CH₂CH₂CH₃ CH₂OCH₃I-148 CH₂CH₂CH₂CH₃ CH₂OCH₃ I-149 CH₂CH₂CH₂CH₂CH₃ CH₂OCH₃ I-150CH₂CH₂CH₂CH₂CH₂CH₃ CH₂OCH₃ I-151 CH₂CH(CH₃)CH₂CH₂CH₃ CH₂OCH₃ I-152CH₂CH(CH₂CH₃)₂ CH₂OCH₃ I-153 CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₂OCH₃ I-154CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₂OCH₃ I-155 CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃CH₂OCH₃ I-156 CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₂OCH₃ I-157CH₂CH₂CH(CH₃)CH₂C(CH₃)₃ CH₂OCH₃ I-158 CH₂CH₂C(CH₃)₂CH₂C(CH₃)₃ CH₂OCH₃I-159 (CH₂)₃—O—CH₃ CH₂OCH₃ I-160 (CH₂)₃—O—CH₂CH₃ CH₂OCH₃ I-161(CH₂)₃—O—CH₂CH₂CH₃ CH₂OCH₃ I-162 (CH₂)₃—O—CH₂CH₂CH₂CH₃ CH₂OCH₃ I-163(CH₂)₃—O—CH₂CH₂CH₂CH₂CH₃ CH₂OCH₃ I-164 (CH₂)₃—O—CH₂CH₂CH₂CH₂CH₂CH₃CH₂OCH₃ I-165 (CH₂)₃—O—CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₂OCH₃ I-166(CH₂)₃—O—CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₂OCH₃ I-167 (CH₂)₃—O—(CH₃)₈CH₃CH₂OCH₃ I-168 (CH₂)₃—O—CH(CH₃)₂ CH₂OCH₃ I-169 (CH₂)₃—O—C(CH₃)₃ CH₂OCH₃I-170 (CH₂)₃—O—CH₂C(CH₃)₃ CH₂OCH₃ I-171 (CH₂)₃—O—CH(CH₃)CH₂C(CH₃)₃CH₂OCH₃ I-172 (CH₂)₃—O—CH(CH₂CH₃)CH₂C(CH₃)₃ CH₂OCH₃ I-173(CH₂)₃—O—CH₂CH(CH₃)CH₂CH(CH₃)₂ CH₂OCH₃ I-174(CH₂)₃—O—CH₂CH(CH₂CH₃)CH₂CH₂CH₃ CH₂OCH₃ I-175(CH₂)₃—O—CH₂CH₂CH(CH₃)CH₂CH(CH₃)₂ CH₂OCH₃ I-176(CH₂)₃—O—CH₂CH₂CH(CH₃)CH₂C(CH₃)₃ CH₂OCH₃ I-177(CH₂)₃—O—CH₂CH₂CH(CH₃)CH₂CH₂CH(CH₃)₂ CH₂OCH₃ I-178(CH₂)₃—O—CH₂CH₂CH(CH₃)(CH₂)₃CH(CH₃)₂ CH₂OCH₃ I-179 CH₃ (CH₂)₃CH₃ I-180CH₂CH₃ (CH₂)₃CH₃ I-181 CH₂CH₂CH₃ (CH₂)₃CH₃ I-182 CH₂CH₂CH₂CH₃ (CH₂)₃CH₃I-183 CH₂CH₂CH₂CH₂CH₃ (CH₂)₃CH₃ I-184 CH₃ (CH₂)₄CH₃ I-185 CH₂CH₃(CH₂)₄CH₃ I-186 CH₂CH₂CH₃ (CH₂)₄CH₃ I-187 CH₂CH₂CH₂CH₃ (CH₂)₄CH₃ I-188CH₂CH₂CH₂CH₂CH₃ (CH₂)₄CH₃ I-189 CH₃ (CH₂)₅CH₃ I-190 CH₂CH₃ (CH₂)₅CH₃I-191 CH₂CH₂CH₃ (CH₂)₅CH₃ I-192 CH₂CH₂CH₂CH₃ (CH₂)₅CH₃ I-193CH₂CH₂CH₂CH₂CH₃ (CH₂)₅CH₃ I-194 CH₃ (CH₂)₆CH₃ I-195 CH₂CH₃ (CH₂)₆CH₃I-196 CH₂CH₂CH₃ (CH₂)₆CH₃ I-197 CH₂CH₂CH₂CH₃ (CH₂)₆CH₃ I-198CH₂CH₂CH₂CH₂CH₃ (CH₂)₆CH₃ I-199 CH₃ (CH₂)₇CH₃ I-200 CH₂CH₃ (CH₂)₇CH₃I-201 CH₂CH₂CH₃ (CH₂)₇CH₃ I-202 CH₂CH₂CH₂CH₃ (CH₂)₇CH₃ I-203CH₂CH₂CH₂CH₂CH₃ (CH₂)₇CH₃ I-204 CH₃ (CH₂)₈CH₃ I-205 CH₂CH₃ (CH₂)₈CH₃I-206 CH₂CH₂CH₃ (CH₂)₈CH₃ I-207 CH₂CH₂CH₂CH₃ (CH₂)₈CH₃ I-208CH₂CH₂CH₂CH₂CH₃ (CH₂)₈CH₃ I-209 CH₂CH₃ CH₂CH₂CH₂CH₂CH₂CH₃ I-210 CH₂CH₃CH₂CH(CH₃)CH₂CH₂CH₃ I-211 CH₂CH₃ CH₂CH₂CH₂CH₂CH₂CH₂CH₃ I-212 CH₂CH₃CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃ I-213 CH₂CH₃ CH₂CH₂CH(CH₃)CH₂C(CH₃)₃ I-214CH₂CH₃ CH₂CH₂C(CH₃)₂CH₂C(CH₃)₃ I-215 CH₂CH₃ CH₂CH₂CH₂CH₂CH₂CH₃ I-216CH₂CH₃ CH₂CH(CH₃)CH₂CH₂CH₃ I-217 CH₂CH═CH₂ CH₃ I-218 CH₂CH═CH₂ CF₃ I-219CH₂CH═CH₂ CH₂CH₃ I-220 CH₂CH═CH₂ CH₂CH₂CH₃ I-221 CH₂CH═CH₂ CH₂OCH₃ I-222CH₂CH═CH₂ (CH₂)₃CH₃ I-223 CH₂CH═CH₂ (CH₂)₄CH₃ I-224 CH₂CH═CH₂ (CH₂)₅CH₃I-225 CH₂CH═CH₂ (CH₂)₆CH₃ I-226 CH₂CH═CH₂ (CH₂)₇CH₃ I-227 CH₂CH═CH₂(CH₂)₈CH₃

Examples of suitable nitriles of the formula II which may be mentionedare those compounds in which R¹ has one of the meanings given in any ofrows I-1 to I-35. Examples of suitable nitriles of the formula II whichmay be mentioned are furthermore those compounds in which R¹ has one ofthe meanings given in rows I-93 to I-126, I-179, I-180 and I-217.

For the process according to the invention, it has furthermore beenfound to be advantageous for R³ in formula III to be C₁-C₈-alkyl orC₁-C₄-alkoxy-C₁-C₄-alkyl. In particular, R³ in formula III isC₁-C₄-alkyl, particularly preferably straight-chain C₁-C₄-alkyl andespecially methyl or ethyl.

Examples of suitable carboxylic esters of the formula III are thecompounds III-1 to III-30 listed in Table 2 in which R² and R³ each havethe meanings given in one row of the table:

TABLE 2 R² R³ III-1 CH₃ CH₃ III-2 C₂H₅ CH₃ III-3 CF₃ CH₃ III-4 CH₂—OCH₃CH₃ III-5 CH₂CH₂CH₃ CH₃ III-6 (CH₂)₃CH₃ CH₃ III-7 (CH₂)₄CH₃ CH₃ III-8(CH₂)₅CH₃ CH₃ III-9 (CH₂)₆CH₃ CH₃ III-10 (CH₂)₇CH₃ CH₃ III-11 (CH₂)₈CH₃CH₃ III-12 CH₂CH(CH₃)CH₂CH₂CH₃ CH₃ III-13 CH₂CH₂CH(CH₃)CH₂C(CH₃)₃ CH₃III-14 CH₂CH₂C(CH₃)₂CH₂C(CH₃)₃ CH₃ III-15 CH₂CH(CH₃)CH₂CH₂CH₃ CH₃ III-16CH₃ CH₂CH₃ III-17 C₂H₅ CH₂CH₃ III-18 CF₃ CH₂CH₃ III-19 CH₂—OCH₃ CH₂CH₃III-20 CH₂CH₂CH₃ CH₂CH₃ III-21 (CH₂)₃CH₃ CH₂CH₃ III-22 (CH₂)₄CH₃ CH₂CH₃III-23 (CH₂)₅CH₃ CH₂CH₃ III-24 (CH₂)₆CH₃ CH₂CH₃ III-25 (CH₂)₇CH₃ CH₂CH₃III-26 (CH₂)₈CH₃ CH₂CH₃ III-27 CH₂CH(CH₃)CH₂CH₂CH₃ CH₂CH₃ III-28CH₂CH₂CH(CH₃)CH₂C(CH₃)₃ CH₂CH₃ III-29 CH₂CH₂C(CH₃)₂CH₂C(CH₃)₃ CH₂CH₃III-30 CH₂CH(CH₃)CH₂CH₂CH₃ CH₂CH₃

In a particularly advantageous manner, the β-ketonitriles which can beobtained according to the invention can be employed for preparing7-aminoazolopyrimidines of the general formula IV.

In formula IV, R¹ and R² have the meanings mentioned above. R⁴ ishydrogen, NH₂ or C₁-C₆-alkyl. X is N or a group C—R⁵ in which R⁵ ishydrogen or C₁-C₆-alkyl. According to a preferred embodiment of theinvention, X is N. According to another preferred embodiment of theinvention, X is CH.

The 7-aminoazolopyrimidines of the general formula IV can be preparedanalogously to known processes of the prior art as described, forexample, in EP-A 141317 and WO2006/087325, for example by reactingr-ketonitriles of the general formula I with an aminoazole compound ofthe formula V

in which R⁴ and X have the meanings mentioned above, or a tautomer of V.

Accordingly, the present invention also relates to a process forpreparing 7-aminoazolopyrimidines of the general formula IV whichcomprises the following process steps:

-   a) Preparation of β-ketonitrile of the general formula I by the    process described herein and-   b) reaction of the β-ketonitrile of the formula I with an aminoazole    compound of the formula V or a tautomer thereof in a manner known    per se, which gives the azolopyrimidine of the formula IV.

The reaction of the β-ketonitrile of the formula I with the aminoazolecompound of the formula or its tautomer is preferably carried out in thepresence of an acid. Suitable acids are, in principle, carboxylic acids,and also organic sulfonic acids. In the case of the sulfonic acids,catalytic amounts are typically employed, which are usually in the rangeof from 1 to 40 mol %, based on one mole of aminoazole of the formula V.In the case of the carboxylic acids, these carboxylic acids may also actas solvents.

Examples of suitable organic sulfonic acids are methanesulfonic acid,trifluoromethanesulfonic acid, benzenesulfonic acid,2,3-dimethylbenzenesulfonic acid, 3,4-dimethylbenzenesulfonic acid andp-toluenesulfonic acid. Suitable organic carboxylic acids are formicacid, acetic acid, propionic acid, 2-methylpropionic acid, benzoic acidand mixtures thereof.

The reaction is preferably carried out in an organic inert solvent.Preference is given to those organic solvents in which the startingmaterials are at least partially or fully soluble. Examples of suitablesolvents are in particular C₁-C₄-alkanols, such as methanol, ethanol,propanol, isopropanol, n-butanol, isobutanol, tert-butanol, the acyclicand alicyclic ethers mentioned above, aromatic hydrocarbons, inparticular alkylaromatics as mentioned above, and also halogenatedaromatics, for example chlorobenzene, dichlorobenzene, furthermoreglycols and glycol monoalkyl ethers, diethylene glycol and theirmonoalkyl ethers, amides and lactams, in particularN,N-di-C₁-C₄-alkylamides of aliphatic carboxylic acids having 1 to 4carbon atoms, such as dimethylformamide, diethylformamide,dibutylformamide, N,N-dimethylacetamide, the carboxylic acids mentionedabove and mixtures of these solvents, and also mixtures of thesesolvents with water. In a preferred embodiment, the inert solventconsists to at least 80% by weight and in particular to at least 90% byweight of aromatic solvents, in particular alkylaromatics.

The reaction of IV with I is preferably carried out at temperatures inthe range of from 80 to 250° C., in particular in the range of from 120to 220° C. and especially in the range of from 150 to 190° C.

In the reaction, the water formed during the reaction is advantageouslyremoved, if appropriate distilled off, for example as an azeotrope withthe solvent used.

In a preferred embodiment of the invention, use is made of aminoazoles Vin which X is N. In another likewise preferred embodiment, use is madeof aminoazoles of the formula V in which X is CH. In the formulae IV andV, R⁴ is preferably hydrogen.

Examples of preferred aminoazoles V are 3-amino-2H-1,2,4-triazole andits tautomers 3-amino-1H-1,2,4-triazole and 3-amino-4H-1,3,4-triazole,and also 3-amino-1H-pyrazole and its tautomer 3-amino-2H-pyrazole.

According to a preferred embodiment, step b) is carried out immediatelyafter step a), without it being necessary to isolate the β-ketonitrile.In particular, for step b) of the process, a solution, obtained afterneutralization of the potassium salt of the β-ketonitrile of the formulaI formed in step a) of the β-ketonitrile I, in an inert organic solventis used. This is in particular a solution in an inert solvent whichconsists to at least 80% by weight and in particular to at least 90% byweight of one or more alkylaromatics.

The reaction of the aminoazole IV or its tautomer can be carried outeither batch-wise or else continuously. It is usually carried outbatch-wise. To this end, the aminoazole IV and the β-ketonitrile aregenerally initially charged in a reaction vessel, if appropriatetogether with solvent and, if appropriate, acid, and the mixture isheated to reaction temperature. If appropriate, part of the solvent isdistilled off together with the water of reaction formed. Suitablereaction vessels are the reactors mentioned for step a) which, ifappropriate, may also be provided with means for distillative removal ofsolvents.

From the reaction mixture obtained in this manner, the compound IV canbe isolated in a customary manner, for example by aqueous work-up, ifappropriate followed by a crystallization for purification or by removalof the solvent and subsequent recrystallization of the product.

The examples below serve to illustrate the invention.

COMPARATIVE EXAMPLE 1 Example 10 of US2004/0171863

At room temperature, 10.88 g of sodium methoxide (0.20 mol), 41.70 g(0.60 mol) of n-butyronitrile and 30.14 g (0.43 mol) of n-butyl acetatewere initially charged in a steel autoclave having a reaction volume of250 ml. The autoclave was flushed with nitrogen, sealed and heated at150° C. for two hours. The solid obtained after cooling was filtered offand dried. This gave 16.9 g of 3-cyanobutan-2-one in the form of itssodium salt (crude product).

16.7 g of the crude product were transferred into the reaction vessel.20 ml of deionized water and 50 ml of ethyl acetate were added, and themixture was stirred. The mixture was then acidified with a total of 11ml of concentrated hydrochloric acid. Afterwards, the pH of the aqueousphase was pH 5. The organic phase was separated off and dried overmagnesium sulfate. After filtration, the organic phase was concentratedto dryness using a rotary evaporator. This gave 9.00 g of a clear orangeliquid which, according to gas chromatogram, consisted of 88.8% of3-cyanopentanone. This corresponds to a total yield of 7.99 g or 27.7%,based on the n-butyl acetate employed.

COMPARATIVE EXAMPLE 2

7.34 g of sodium methoxide, 48.5 g of xylene, 64 g (0.40 mol) ofdecanenitrile and 17.9 g (0.17 mol) of ethyl propionate were initiallycharged in a steel autoclave having a reaction volume of 250 ml. Theautoclave was flushed with nitrogen, sealed and then heated at 150° C.for two hours. The sodium salt obtained after cooling was filtered offand dried. In this manner, 38.8 g of dry crude product were obtainedwhich were filled into a glass flask, and 27.00 g of deionized water and60.84 g of ethyl acetate were added. The mixture was then acidified with14.50 ml of concentrated hydrochloric acid. After the addition ofhydrochloric acid, the pH of the aqueous phase was pH 4.5. The organicphase was separated off, dried over magnesium sulfate, filtered and thenconcentrated to dryness using a rotary evaporator. This gave 62.80 g ofa crude product which, according to gas chromatogram, consisted of 78.2%unreacted nitrile and 11.27% of the desired product.

Examples according to the invention

EXAMPLE 1 2-(2-Methoxyacetyl)decanonitrile

In a stirred vessel fitted with reflux condenser and dropping funnel,199.96 g of solid potassium methoxide were initially charged, and 318 gof o-xylene were added. 15 g of ethanol were added, and the suspensionwas heated to reflux. A mixture of 170 g of decanonitrile and 180.8 g ofethyl methoxy acetate was then added via the dropping funnel over aperiod of 10 min. After the addition had ended, stirring was continuedfor 6 h, and the mixture was then cooled to 105° C. 373 g of water werethen added, and the mixture was adjusted to pH 4 by addition of about388 g of 20% strength hydrochloric acid. The temperature was set to 70°C., and the (lower) aqueous phase was removed. The organic phase waswashed with another 186 g of water. After removal of the aqueous phase,the organic phase was concentrated to half of its original volume inorder to remove the water. This gave 235.5 g of a pale yellow solutionhaving a content of product of value of 62% a/a (GC), which can bereacted further as such. For purification, the compound was distilledunder high vacuum, with the product passing over at 120 to 134° C./1mbar.

¹H-NMR (CDCl₃): 0.89 (t, 3H); 1.2-1.55 (m, 12H); 1.88 (m, 2H); 3.45 (s,3H), 3.75 (dd, 1H); 4.20 (s, 2H).

EXAMPLE 2 2-Acetyldecanonitrile

In a stirred vessel fitted with reflux condenser and dropping funnel,317 g of o-xylene were initially charged, 198.96 g of solid potassiummethoxide were added and the mixture was heated at reflux. A mixture of170 g of decanonitrile and 133.9 g of ethyl acetate was then added viathe dropping funnel over a period of 10 min. After the addition hadended, stirring was continued for 4 h, and the mixture was then cooledto 105° C. 372 g of water were then added, and the mixture was adjustedto pH 4.3 by addition of about 470 g of 20% strength hydrochloric acid.The temperature was set to 65° C., and the (lower) aqueous phase wasremoved. The organic phase was washed with another 186 g of water. Afterremoval of the aqueous phase, the organic phase was concentrated toabout half of its original volume to remove the water. This gave 211.7 gof a light-yellow solution having a content of product of value of 66.8%a/a (GC), which solution can be reacted further as such. Forpurification, the compound was distilled under high vacuum, with theproduct passing over at 106 to 121° C./1 mbar.

¹H-NMR: 0.9 (t, 3H); 1.1-1.7 (m, 12H); 1.9 (m, 2H); 2.38 (s, 3H); 3.40(dd, 1H).

EXAMPLE 3 2-Propionylpent-4-enenitrile

In a 20 l jacketed reactor fitted with heating/cooling circuit andreflux condenser, 3500 g of potassium tert-butoxide were initiallycharged, and 6316 g of tetrahydrofuran was added. At a temperature of atmost 10° C., a mixture of 1200 g of pentenenitrile and 1651 g of ethylpropionate was then pumped in over a period of 75 min. Stirring wascontinued at 8 to 10° C. for 3 h and then at 15° C. overnight. Themixture was then adjusted to pH of 3.8 by pumping in 6316 g of 20%strength hydrochloric acid, with the temperature increasing to 48° C.2400 ml of water and 4000 ml of o-xylene were then added. The aqueous(lower) phase was then removed, and the organic phase was washed twomore times with in each case 2400 ml of water. What remained were 14650g of organic phase. Concentration on a rotary evaporator at 60° C. and10 mbar gave 1873 g of an amber product having a content of 87.4% a/a(GC), which was reacted further as such.

¹H-NMR: 1.12 (s, 3H); 2.52 (q)+2.75 (m) (together 4H); 3.50 (t, 1H);5.25 (m, 2H); 5.80 (m, 1H).

EXAMPLE 4 2-Propionyldecanonitrile

In a stirred vessel fitted with reflux condenser and dropping funnel,724 g of o-xylene were initially charged, 454.2 g of solid potassiummethoxide were added and the mixture was heated at reflux. Initially 10%of a mixture of 392.0 g of decanonitrile and 360.6 g of ethyl propionatewere then added via the dropping funnel over a period of 1 min, and themixture was stirred for 15 min. The remainder of the mixture was thenmetered in over a period of 10 min. After the addition had ended, themixture was stirred under gentle reflux for another 4 h and then cooledto 105° C. The mixture was discharged into 848 g of water in a secondtank and adjusted to a pH of 6 by addition of about 1020 g of 20%strength hydrochloric acid. The temperature was set to 80° C., and the(lower) aqueous phase was removed. This gave 1316 g of a light-yellowsolution having a content of product of value of 37.6% a/a (GC), whichcan be reacted further as such. For purification, the compound wasdistilled under high vacuum, with the product passing over at 130 to140° C./1 mbar. ¹H-NMR: 0.9 (t, 3H); 1.11 (t, 3H), 1.2-1.4 (m, 10H);1.4-1.55 (m, 2H); 1.8-2.0 (m, 2H); 2.75 (q, 2H), 3.40 (t, 1H).

General Procedure A for Preparing β-Ketonitriles of the General FormulaI:

587 g (7.96 mol) of potassium methoxide, 940 g of ortho-xylene and 25 gof ethanol are initially charged in a reaction vessel provided withstirrer, reflux condenser and nitrogen inlet, and the mixture is then,under nitrogen, heated at reflux (bath temperature 150° C., internaltemperature 132° C.). Via two separate feeds, over a period of 21minutes, 3.23 mol of nitrile of the formula I and 4.4 mol of ester ofthe formula II are then added simultaneously to the reaction vessel,with the temperature being maintained. The mixture is then heated atreflux for a further four hours and subsequently cooled to 105° C. Thehot content of the reaction flask is then discharged into a reactiontank containing 1190 g of water. The resulting mixture is stirred, thenadjusted to pH 4-5 using 1350 g of 20% by weight strength aqueoushydrochloric acid and stirred for a further 15 min. Using 20% by weightstrength hydrochloric acid, the aqueous phase is adjusted to pH 4 to 5,and then stirred for 15 minutes. The aqueous phase is then separatedoff, and the organic phase is washed with a total of 1100 g of deionizedwater. Using a rotary evaporator, the organic phase is then concentratedto about 75% of its original volume.

For purification of the compound, the solvent is initially distilled offunder reduced pressure. The residue that remained is then rectifiedunder high vacuum. This gives the compounds of the formula I as mainfraction in the form of colorless to pale yellow oils. The unreactedpart of the starting material is obtained as prefractions suitable forrecycling.

In this manner, it is possible to prepare the following compounds of theformula I, unless indicated otherwise:

Yield Ex. R¹ R² [%]¹⁾ 1 CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₂OCH₃ 59.2 2CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₃ 66.1 3 CH₂CH═CH₂ CH₂CH₃ 81.0 4CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₂CH₃ 92.0 5 CH₂CH₂CH(CH₃)CH₂C(CH₃)₃ CH₃ 6CH₂CH₂C(CH₃)₂CH₂C(CH₃)₃ CH₃ 7 CH₂CH₂CH₂CH₂CH₂CH₃ CF₃ 8CH₂CH(CH₃)CH₂CH₂CH₃ CF₃ 9 CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CF₃ 10CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CF₃ 11 CH₂CH₂CH(CH₃)CH₂C(CH₃)₃ CF₃ 12CH₂CH₂C(CH₃)₂CH₂C(CH₃)₃ CF₃ 13 CH₂CH₂CH₂CH₂CH₂CH₃ CH₂CH₃ 14CH₂CH(CH₃)CH₂CH₂CH₃ CH₂CH₃ 15 CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₂CH₃ 16CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₃ 17 CH₂CH₂CH(CH₃)CH₂C(CH₃)₃ CH₂CH₃ 18CH₂CH₂C(CH₃)₂CH₂C(CH₃)₃ CH₂CH₃ 19 CH₂CH₂CH₂CH₂CH₂CH₃ CH₂CH₂CH₃ 20CH₂CH(CH₃)CH₂CH₂CH₃ CH₂CH₂CH₃ 21 CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₂CH₂CH₃ 22CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₂CH₂CH₃ 23 CH₂CH₂CH(CH₃)CH₂C(CH₃)₃ CH₂CH₂CH₃24 CH₂CH₂C(CH₃)₂CH₂C(CH₃)₃ CH₂CH₂CH₃ 25 CH₂CH₂CH₂CH₂CH₂CH₃ CH₂OCH₃ 26CH₂CH(CH₃)CH₂CH₂CH₃ CH₂OCH₃ 27 CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₂OCH₃ 28CH₂CH₂CH₂CH₂CH₂CH₃ CH₃ 29 CH₂CH₂CH(CH₃)CH₂C(CH₃)₃ CH₂OCH₃ 30CH₂CH₂C(CH₃)₂CH₂C(CH₃)₃ CH₂OCH₃ 31 CH₂CH₃ CH₂CH₂CH₂CH₂CH₂CH₃ 32 CH₂CH₃CH₂CH(CH₃)CH₂CH₂CH₃ 33 CH₂CH₃ CH₂CH₂CH₂CH₂CH₂CH₂CH₃ 34 CH₂CH₃CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃ 35 CH₂CH₃ CH₂CH₂CH(CH₃)CH₂C(CH₃)₃ 36 CH₂CH₃CH₂CH₂C(CH₃)₂CH₂C(CH₃)₃ 37 CH₂CH═CH₂ CH₃ 38 CH₂CH═CH₂ CF₃ 39CH₂CH(CH₃)CH₂CH₂CH₃ CH₃ 40 CH₂CH═CH₂ CH₂CH₂CH₃ 41 CH₂CH═CH₂ CH₂OCH₃ 42CH₂CH═CH₂ (CH₂)₃CH₃ 43 CH₂CH═CH₂ (CH₂)₄CH₃ 44 CH₂CH═CH₂ (CH₂)₅CH₃ 45CH₂CH═CH₂ (CH₂)₆CH₃ 46 CH₂CH═CH₂ (CH₂)₇CH₃ 47 CH₂CH═CH₂ (CH₂)₈CH₃¹⁾based on the nitrile II

EXAMPLE 48 5-Ethyl-6-octyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-ylamine

In a 2.5 l jacketed vessel fitted with condenser and water separator,737 g of o-xylene was initially charged, and 39.5 g of chlorosulfonicacid was added. 191.2 g of 3-amino-1,2,4-triazole and 1254 g of asolution of 2-propionyldecanonitrile (37.7% by weight in o-xylene) wereadded, and the mixture was heated to reflux. The mixture was stirredunder reflux for 12 hours, and the water of reaction formed was removedvia a phase separator. Once no more water was separated off, the mixturewas cooled to 140° C. and 59.4 g of triethylamine were added. On furthercooling, the product precipitated in the form of colorless crystals. Ata temperature 105° C., 152.8 g of methanol were added. The mixture wascooled further to 20° C., and the solid formed was separated off. Thefiltercake was washed with a mixture of 850 g of methanol and 119 g ofwater and then dried under reduced pressure. This gave 525.5 g ofcolorless crystals having a content of 98.3% a/a (HPLC). The titlecompound was obtained as a mixture of two modifications having meltingpoints of 199° C. and 201° C., respectively. Yield: 83.0%.

EXAMPLE 49 6-Allyl-5-ethyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-ylamine

In a 20 l jacketed vessel fitted with reflux condenser and waterseparator, 14650 g of o-xylene were initially charged, and 411 g ofchlorosulfonic acid were added. 2074 g of 3-amino-1,2,4-triazole and3690 g of a solution of 2-propionylpent-4-enenitrile (87.4% in o-xylene)were added, and the mixture was heated to reflux. The mixture wasstirred under reflux for 14 hours, and the water of reaction formed wasremoved via a phase separator. Once no more water separated off, themixture was cooled to 130° C. and 634 g of triethylamine were added. Onfurther cooling, the product precipitated in the form of colorlesscrystals. At a temperature of 100° C., 2350 g of isopropanol were added.The mixture was cooled further to 20° C., and the solid formed wasseparated off. The filtercake was washed with 1500 ml of a 1:1 mixtureof isopropanol and water and then dried under reduced pressure. Thisgives 4057 g of a colorless powder. Melting point: 258° C.(decomposition), ¹H-NMR: 1.35 (t, 3H); 2.88 (q, 2H); 3.45 (d, 2H); 5.09(d, 2H); 5.20 (d, 2H); 5.6 (s, broad, 2H); 5.8-6.0 (m, 1H); 8.30 (s,1H). Yield: 84.0%.

EXAMPLE 50

Analogously to Example 48,5-methoxymethyl-6-octyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-ylamine wasprepared from 2-(2-methoxyacetyl)decanonitrile. This gave colorlesscrystals having a melting point of from 181 to 182° C. Yield: 85.1%.

EXAMPLE 51

Analogously to Example 48,5-methyl-6-octyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-ylamine was preparedfrom 2-acetyldecanonitrile. This gave colorless crystals. The titlecompound was obtained as a mixture of two modifications having meltingpoints of 199 to 200° C. and 216 to 217° C., respectively. Yield: 79.2%.

General Procedure B for Preparing 7-Aminoazolopyrimidines of the GeneralFormula IV Variant 1:

A solution of 97 mmol of a ketonitrile according to procedure A isdissolved in 60 ml of mesitylene and, together with 8.1 g (97 mmol) of3-amino-1,2,4-triazole (or 97 mmol of 3-aminopyrazole) and 3.8 g of4-toluenesulfonic acid, heated at 180° C. for three hours, during whicha little solvent and the reaction water distils off. The solvent is thendistilled off completely, and the residue is taken up in methylenechloride. After washing with saturated aqueous NaHCO₃ solution andwater, the organic phase is dried, the solvent is removed and theresidue is digested with diethyl ether. The compounds of the formula IVremain as colorless to pale yellow crystals or as colorless to paleyellow oils.

Variant 2:

At room temperature, oleum (18.4 mmol SO₃) is added to 60 ml ofo-xylene, and the mixture is then heated at reflux together with 97 mmolof a ketonitrile according to procedure A, 8.1 g (97 mmol) of3-amino-1,2,4-triazole (or 97 mmol of 3-amino-pyrazole) and 3.8 g of4-toluenesulfonic acid for eight hours, and during this time, the waterof reaction is removed. The solvent is then distilled off completely,and the residue is taken up in methylene chloride. After washing withsaturated NaHCO₃ solution and water, the organic phase is dried andfreed from the solvent and the residue is digested with diethyl ether.The compounds of the formula IV are obtained as colorless to pale yellowcrystals or as colorless to pale yellow oils.

Variant 3:

At room temperature, 2.14 g (18.4 mmol) of chlorosulfonic acid are addedto 60 ml of o-xylene, and the mixture is then heated at reflux togetherwith 97 mmol of a ketonitrile according to procedure A, 8.1 g (97 mmol)of 3-amino-1,2,4-triazole (or 97 mmol of 3-aminopyrazole) and 3.8 g of4-toluenesulfonic acid for ten hours, and the water of reaction formedis removed. The mixture is then cooled to 20° C. over a period of 10 h.The suspension formed is filtered off, and the filtercake is then washedwith methanol and water. After drying under reduced pressure, thecompounds of the formula IV are obtained as colorless to pale yellowcrystals or as colorless to pale yellow oils.

In this manner, it is possible to prepare the following compounds of theformula IV, unless indicated otherwise:

Ex. R¹ R² X R⁴ 52 CH₂CH₂CH₂CH₂CH₂CH₃ CH₃ N H 53 CH₂CH(CH₃)CH₂CH₂CH₃ CH₃N H 54 CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₃ N H 55 CH₂CH₂CH(CH₃)CH₂C(CH₃)₃ CH₃ N H56 CH₂CH₂C(CH₃)₂CH₂C(CH₃)₃ CH₃ N H 57 CH₂CH₂CH₂CH₂CH₂CH₃ CF₃ N H 58CH₂CH(CH₃)CH₂CH₂CH₃ CF₃ N H 59 CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CF₃ N H 60CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CF₃ N H 61 CH₂CH₂CH(CH₃)CH₂C(CH₃)₃ CF₃ N H 62CH₂CH₂C(CH₃)₂CH₂C(CH₃)₃ CF₃ N H 63 CH₂CH₂CH₂CH₂CH₂CH₃ CH₂CH₃ N H 64CH₂CH(CH₃)CH₂CH₂CH₃ CH₂CH₃ N H 65 CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₂CH₃ N H 66CH₂CH₂CH(CH₃)CH₂C(CH₃)₃ CH₂CH₃ N H 67 CH₂CH₂C(CH₃)₂CH₂C(CH₃)₃ CH₂CH₃ N H68 CH₂CH₂CH₂CH₂CH₂CH₃ CH₂CH₂CH₃ N H 69 CH₂CH(CH₃)CH₂CH₂CH₃ CH₂CH₂CH₃ N H70 CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₂CH₂CH₃ N H 71 CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃CH₂CH₂CH₃ N H 72 CH₂CH₂CH(CH₃)CH₂C(CH₃)₃ CH₂CH₂CH₃ N H 73CH₂CH₂C(CH₃)₂CH₂C(CH₃)₃ CH₂CH₂CH₃ N H 74 CH₂CH₂CH₂CH₂CH₂CH₃ CH₂OCH₃ N H75 CH₂CH(CH₃)CH₂CH₂CH₃ CH₂OCH₃ N H 76 CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₂OCH₃ N H77 CH₂CH₂CH(CH₃)CH₂C(CH₃)₃ CH₂OCH₃ N H 78 CH₂CH₂C(CH₃)₂CH₂C(CH₃)₃CH₂OCH₃ N H 79 CH₂CH₂CH₂CH₂CH₂CH₃ CH₃ N NH₂ 80 CH₂CH(CH₃)CH₂CH₂CH₃ CH₃ NNH₂ 81 CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₃ N NH₂ 82 CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₃ NNH₂ 83 CH₂CH₂CH(CH₃)CH₂C(CH₃)₃ CH₃ N NH₂ 84 CH₂CH₂C(CH₃)₂CH₂C(CH₃)₃ CH₃N NH₂ 85 CH₂CH₂CH₂CH₂CH₂CH₃ CF₃ N NH₂ 86 CH₂CH(CH₃)CH₂CH₂CH₃ CF₃ N NH₂87 CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CF₃ N NH₂ 88 CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CF₃ N NH₂89 CH₂CH₂CH(CH₃)CH₂C(CH₃)₃ CF₃ N NH₂ 90 CH₂CH₂C(CH₃)₂CH₂C(CH₃)₃ CF₃ NNH₂ 91 CH₂CH₂CH₂CH₂CH₂CH₃ CH₂CH₃ N NH₂ 92 CH₂CH(CH₃)CH₂CH₂CH₃ CH₂CH₃ NNH₂ 93 CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₂CH₃ N NH₂ 94 CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃CH₂CH₃ N NH₂ 95 CH₂CH₂CH(CH₃)CH₂C(CH₃)₃ CH₂CH₃ N NH₂ 96CH₂CH₂C(CH₃)₂CH₂C(CH₃)₃ CH₂CH₃ N NH₂ 97 CH₂CH₂CH₂CH₂CH₂CH₃ CH₂CH₂CH₃ NNH₂ 98 CH₂CH(CH₃)CH₂CH₂CH₃ CH₂CH₂CH₃ N NH₂ 99 CH₂CH₂CH₂CH₂CH₂CH₂CH₃CH₂CH₂CH₃ N NH₂ 100 CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₂CH₂CH₃ N NH₂ 101CH₂CH₂CH(CH₃)CH₂C(CH₃)₃ CH₂CH₂CH₃ N NH₂ 102 CH₂CH₂C(CH₃)₂CH₂C(CH₃)₃CH₂CH₂CH₃ N NH₂ 103 CH₂CH₂CH₂CH₂CH₂CH₃ CH₂OCH₃ N NH₂ 104CH₂CH(CH₃)CH₂CH₂CH₃ CH₂OCH₃ N NH₂ 105 CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₂OCH₃ NNH₂ 106 CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₂OCH₃ N NH₂ 107CH₂CH₂CH(CH₃)CH₂C(CH₃)₃ CH₂OCH₃ N NH₂ 108 CH₂CH₂C(CH₃)₂CH₂C(CH₃)₃CH₂OCH₃ N NH₂ 109 CH₂CH₂CH₂CH₂CH₂CH₃ CH₃ CH H 110 CH₂CH(CH₃)CH₂CH₂CH₃CH₃ CH H 111 CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₃ CH H 112 CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃CH₃ CH H 113 CH₂CH₂CH(CH₃)CH₂C(CH₃)₃ CH₃ CH H 114CH₂CH₂C(CH₃)₂CH₂C(CH₃)₃ CH₃ CH H 115 CH₂CH₂CH₂CH₂CH₂CH₃ CF₃ CH H 116CH₂CH(CH₃)CH₂CH₂CH₃ CF₃ CH H 117 CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CF₃ CH H 118CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CF₃ CH H 119 CH₂CH₂CH(CH₃)CH₂C(CH₃)₃ CF₃ CH H120 CH₂CH₂C(CH₃)₂CH₂C(CH₃)₃ CF₃ CH H 121 CH₂CH₂CH₂CH₂CH₂CH₃ CH₂CH₃ CH H122 CH₂CH(CH₃)CH₂CH₂CH₃ CH₂CH₃ CH H 123 CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₂CH₃ CHH 124 CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₂CH₃ CH H 125 CH₂CH₂CH(CH₃)CH₂C(CH₃)₃CH₂CH₃ CH H 126 CH₂CH₂C(CH₃)₂CH₂C(CH₃)₃ CH₂CH₃ CH H 127CH₂CH₂CH₂CH₂CH₂CH₃ CH₂CH₂CH₃ CH H 128 CH₂CH(CH₃)CH₂CH₂CH₃ CH₂CH₂CH₃ CH H129 CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₂CH₂CH₃ CH H 130 CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃CH₂CH₂CH₃ CH H 131 CH₂CH₂CH(CH₃)CH₂C(CH₃)₃ CH₂CH₂CH₃ CH H 132CH₂CH₂C(CH₃)₂CH₂C(CH₃)₃ CH₂CH₂CH₃ CH H 133 CH₂CH₂CH₂CH₂CH₂CH₃ CH₂OCH₃ CHH 134 CH₂CH(CH₃)CH₂CH₂CH₃ CH₂OCH₃ CH H 135 CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₂OCH₃CH H 136 CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃ CH₂OCH₃ CH H 137CH₂CH₂CH(CH₃)CH₂C(CH₃)₃ CH₂OCH₃ CH H 138 CH₂CH₂C(CH₃)₂CH₂C(CH₃)₃ CH₂OCH₃CH H 139 CH₂CH═CH₂ CH₃ N H 140 CH₂CH═CH₂ CF₃ N H 141 CH₂CH═CH₂ CH₂CH₂CH₃N H 142 CH₂CH═CH₂ CH₂OCH₃ N H 143 CH₂CH═CH₂ (CH₂)₃CH₃ N H 144 CH₂CH═CH₂(CH₂)₄CH₃ N H 145 CH₂CH═CH₂ (CH₂)₅CH₃ N H 146 CH₂CH═CH₂ (CH₂)₆CH₃ N H147 CH₂CH═CH₂ (CH₂)₇CH₃ N H 148 CH₂CH═CH₂ (CH₂)₈CH₃ N H 149 CH₂CH═CH₂CH₃ CH H 150 CH₂CH═CH₂ CF₃ CH H 151 CH₂CH═CH₂ CH₂CH₃ CH H 152 CH₂CH═CH₂CH₂CH₂CH₃ CH H 153 CH₂CH═CH₂ CH₂OCH₃ CH H 154 CH₂CH═CH₂ (CH₂)₃CH₃ CH H155 CH₂CH═CH₂ (CH₂)₄CH₃ CH H 156 CH₂CH═CH₂ (CH₂)₅CH₃ CH H 157 CH₂CH═CH₂(CH₂)₆CH₃ CH H 158 CH₂CH═CH₂ (CH₂)₇CH₃ CH H 159 CH₂CH═CH₂ (CH₂)₈CH₃ CH H²⁾ based on the ketonitrile of the formula I

1. A process for preparing an azolopyrimidine of the formula IV

in which R¹ and R² have one of the meanings given in claim 1, R⁴ ishydrogen, NH₂ or C₁-C₆-alkyl and X is N or a group C—R⁵, where R⁵ ishydrogen or C₁-C₆-alkyl; which comprises: a) preparing the β-ketonitrileof claim 11 and b) reacting the β-ketonitrile with an aminoazolecompound of the formula V

or a tautomer thereof, in a known manner, giving the azolopyrimidine ofthe formula IV.
 2. The process as claimed in claim 1 where the reactionmixture obtained in step a), which comprises the β-ketonitrile of theformula II, is neutralized and, without further purification, reacted instep b) with the aminoazole compound of the formula V.